As the external surface of a body, skin is under frequent assaults from environmental agents. To maintain its integrity and function, immune cells in the skin are tightly regulated to tolerate harmless antigens but respond to dangerous assaults. Skin-resident T cells are unique populations of immune cells with memory cell-like properties (Clark, R. A., 2010, J Invest Dermatol 130:362-370). Among them, the resident CD4+ regulatory T (Treg) cells are critical to maintain the immune homeostasis of healthy skin (Sather, B. D., et al., 2007, J Exp Med 204:1335-1347 and Dudda, J. C., et al., 2008, J Exp Med 205:1559-1565), while the resident memory effector T (Teff) cells could provide faster immune responses to infection in the skin than those of the circulation (Gebhardt, T., et al., 2009, Nat Immunol 10:524-530, Jiang, X., et al., 2012, Nature 483:227-231 and Mackay, L. K., et al., 2012, Proc Natl Acad Sci USA 109:7037-7042). The antigen encounter in the skin might also induce memory Treg cells to counterbalance the Teff response (Rosenblum, M. D., et al., 2012, Nature 480:538-542). Dysregulation of Treg and Teff cells in the skin is associated with allergy and other skin inflammatory diseases.
CCR10 and its ligand CCL27 is the most skin-specific chemokine/receptor pair (Zlotnik, A., et al., 2012, Immunity 36:705-716). With CCL27 constitutively expressed in healthy skin and further upregulated in inflamed skin in patients of psoriasis and dermatitis and animal models, CCR10/CCL27 have been implicated in migration of skin T cells under both healthy and disease conditions (Morales, J., et al., 1999, Proc Natl Acad Sci USA 96:14470-14475, Homey, B., et al., 2000, J Immunol 164:3465-3470, Jarmin, D. I., et al., 2000 J Immunol 164:3460-3464 and Homey, B., et al., 2002, Nat Med 8:157-165). In humans, all blood CCR10+ T cells display memory cell markers, co-express the skin-homing molecule cutaneous lymphocyte antigen (CLA) and respond to chemoattraction of CCL27, suggesting a role of CCR10/CCL27 in recruitment of memory T cells into the skin (Morales, J., et al., 1999, Proc Natl Acad Sci USA 96:14470-14475, Homey, B., et al., 2002, Nat Med 8:157-165 and Soler, D., et al., 2003, Blood 101:1677-1682). However, immunohistochemical staining in one early study found only scattered CCR10+ cells in healthy skin of humans (Homey, B., et al., 2002, Nat Med 8:157-165). Instead, most T cells of inflamed skin of psoriatic and dermatitic patients express CCR10. Since CCL27 was also upregulated in the inflamed skin, it was suggested that CCR10/CCL27 are involved in migration of T cells during the skin inflammation and inhibiting CCR10/CCL27-derived signals could be used to treat skin inflammatory diseases (Homey, B., et al., 2002, Nat Med 8:157-165). But the flow cytometric analysis of T cells isolated from the allergen and bacterial chancroid-induced inflamed human skin in another study found only a small percentage of CCR10+ cells, suggesting that CCR10 is unlikely critical for migration of most T cells during the skin inflammation (Soler, D., et al., 2003, Blood 101:1677-1682). A recent study reported that CCR10 is co-expressed on half of human blood CCR8+ T cells, a population with the skin-homing potential, but T cells migrating out of the healthy human skin do not express CCR10 although non-migrating skin-resident T cells were not assessed (McCully, M. L., et al., 2012, Blood 120:4591-4598). CCR10+ CD4+ T cells of human blood are also enriched with IL-22-producing cells that also preferentially express CCR6, another chemokine receptor associated with skin localization (Duhen, T., et al., 2009, Nat Immunol 10:857-863 and Trifari, S., et al., 2009, Nat Immunol 10:864-871). Up to now, the role of CCR10/CCL27 as homeostatic or inflammatory regulators of skin T cells remains unclear.
CCR10 was also expressed on skin-resident innate lymphoid cells (ILC) (Salimi, M., et al., 2013, J Exp Med 210:2939-50). ILC cells are a family of innate lymphocytes preferentially enriched in barrier tissues such as the intestine and skin and involved in the local tissue homeostasis and inflammation (Spits, H., et al., 2012. Annu Rev Immunol 30:647-675). ILCs do not express cell-surface markers associated with other immune cell lineages (lineage marker negative or LIN−) but express the common hematopoietic lineage marker CD45 and surface molecules commonly associated with lymphocytes such as CD90 and CD127 (Spits, H., et al., 2012. Annu Rev Immunol 30:647-675). Based on their developmental pathways and functional potentials in analog to the different T helper cell (Th) subsets, ILCs were divided into three major groups (ILC1-3) (Spits, H., et al., 2013, Nat Rev Immunol 13:145-149). ILC1 comprises natural killer (NK) cells and other ILCs that produce IFN-γ. ILC2 cells predominantly express Th2-type cytokines such as IL-5 and IL-15, and ILC3 cells produce Th-17/22 type cytokines such as IL-17 and IL-22. Through the production of unique cytokines and direct cell-cell interaction, ILCs have been reported to act on various other subsets of immune cells, such as T cells, mast cells, eosinophils and macrophages, and epithelial cells to regulate homeostasis as well as inflammation in barrier tissues (Withers, D. R., et al. 2012. J Immunol 189:2094-2098; Hanash, A. M., et al, 2012, Immunity 37:339-350; Dudakov, J. A., et al, 2012, Science 336:91-95; Pantelyushin, S., et al., 2012, J Clin Invest 122:2252-2256; Roediger, B., et al., 2013, Nat Immunol 14:564-573; Kim, B. S., et al, 2013, Sci Transl Med 5:170ra116; Imai, Y., et al, 2013, Proc Natl Acad Sci USA 110:13921-13926). However, roles of CCR10 in regulating localization and function of ILCs are not clear.
Animal studies also provide complex and sometimes seemingly contradicting results on functions of CCR10/CCL27. In a mouse model of the allergen DNFB (2,4-dinitro-1-fluorobenzene)-induced contact hypersensitive response (CHS), one study found that the antibody neutralization of CCL27 reduced the skin T cell recruitment and inflammation, suggesting a pivotal role of the CCL27/CCR10 axis in T cell-mediated skin inflammation (Homey, B., et al., 2002, Nat Med 8:157-165). Similarly, in the keratin-14 promoter-driven IL-4 transgenic mouse model of atopic dermatitis, subcutaneous injection of anti-CCL27 antibodies reduced inflammation (Chen, L., et al., 2006, Int Immunol 18:1233-1242). However, the anti-CCL27 antibody treatment did not affect recruitment of transferred CD4+ T cells into the DNFB-inflamed skin or allergens-induced CHS responses in other studies (Reiss, Y., et al., 2001, J Exp Med 194:1541-1547 and Mirshahpanah, P., et al., 2008, Exp Dermatol 17:30-34). Recently, it was reported that CCR10-sufficent and -knockout CD4+ T cells migrate similarly to the cognate-antigen-stimulated skin, demonstrating directly that CCR10 is not critical for the T cell infiltration into inflamed skin (Tubo, N. J., et al., 2011, Am J Pathol 178:2496-2503). Up to now, the role of CCR10 in regulation of skin immune homeostasis and responses in vivo remains unknown.
CCR10 could be also potentially involved in regulation of immune homeostasis and response in intestines. In both large and small intestines, the mucosa-specific ligand for CCR10, CCL28, is highly expressed by intestinal epithelial cells (Pan, J., et al, 2000, J Immunol 165:2943-2949; Wang, W., et al, 2000, J Biol Chem 275:22313-22323). CCR10 was previously found to express on all IgA-antibody secreting cells (IgA-ASC) and suggested to regulate their intestinal migration (Kunkel, E. J., et al, 2003, J Clin Invest 111:1001-1010). However, anti-CCL28 antibody blockage or CCR10-knockout had little effects on IgA responses to infections or homeostatic productions of IgA antibodies in intestines (Feng, N., et al, 2006, J Immunol 176:5749-5759; Morteau, O., et al, 2008, J Immunol 181:6309-6315; Hu, S., et al, 2011, Proc Natl Acad Sci USA 108:E1035-1044). We found recently that CCR10 is critical in the IgA memory responses against infections in intestines (Hu, S., et al, 2011, Proc Natl Acad Sci USA 108:E1035-1044), suggesting potentially important roles of CCR10 in intestinal immune responses. Related with this, expression of the ligand CCL28 was upregulated in inflamed intestines (35)(25). However, up to now, functional importance of CCR10 in intestinal homeostatic regulation and diseases is unknown.
There is a need in the art to better understand the role of CCR10 in the immune system. In addition, there is a need in the art for the development of successful therapeutics for the treatment of skin and intestinal diseases. The present invention satisfies the need in the art for development of new approaches for efficient means to induce an immune response to treat skin and intestinal diseases.